Bottom Line:
For the interventional study, the animals were chronically treated with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin, at 5 mg/kg.Primary hippocampal neuronal cultures were used to investigate the mechanisms underlying the dysfunction of PV interneurons.Notably, these abnormalities could be rescued by apocynin treatment.

Background: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by many pathological events, including neuroinflammation and oxidative stress damage. Increasing evidence suggests that parvalbumin (PV) interneurons play a key role in the cognitive process, whereas the dysfunction of these interneurons has been implicated in a number of major psychiatric disorders. Here, we aimed to investigate whether enhanced inflammation and oxidative stress-mediated PV interneuron phenotype loss plays a role in sepsis-induced cognitive impairments.

Methods: Male C57BL/6 mice were subjected to cecal ligation and puncture or sham operation. For the interventional study, the animals were chronically treated with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin, at 5 mg/kg. The mice were euthanized at the indicated time points, and the brain tissues were harvested for determination of the PV, membrane subunit of NADPH oxidase gp91(phox), and markers of oxidative stress (4-hydroxynonenal and malondialdehyde) and inflammation (tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-6, and IL-10). A separate cohort of animals was used to evaluate the behavioral alterations by the open field and fear conditioning tests. Primary hippocampal neuronal cultures were used to investigate the mechanisms underlying the dysfunction of PV interneurons.

Results: Sepsis resulted in cognitive impairments, which was accompanied by selective phenotype loss of PV interneurons and increased gp91(phox), 4-hydroxynonenal, malondialdehyde, IL-1β, and IL-6 expressions. Notably, these abnormalities could be rescued by apocynin treatment.

Conclusion: Selective phenotype loss of PV interneurons, as a result of NADPH oxidase 2 (Nox2) activation, might partly contribute to cognitive impairments in a mouse model of SAE.

Fig6: Double-immunofluorescence staining to detect co-localization of PV and 8-OH-dG in the CA1 and CA3 regions of the hippocampus at day 14 after operation. a Representative images of PV (green) and 8-OH-dG (red) in the CA1 and CA3 regions of the hippocampus. b The PV immunoreactivity was decreased and the 8-OH-dG immunoreactivity was increased in the PV interneurons in the CA1 and CA3 regions of the hippocampus in the CLP + vehicle group compared with the sham groups, whereas apocynin treatment reversed these abnormities. Data are presented as mean ± SEM (n = 6). #p < 0.05 vs the sham groups; *p < 0.05 vs the CLP + vehicle group. Scale bar = 100 μm

Fig6: Double-immunofluorescence staining to detect co-localization of PV and 8-OH-dG in the CA1 and CA3 regions of the hippocampus at day 14 after operation. a Representative images of PV (green) and 8-OH-dG (red) in the CA1 and CA3 regions of the hippocampus. b The PV immunoreactivity was decreased and the 8-OH-dG immunoreactivity was increased in the PV interneurons in the CA1 and CA3 regions of the hippocampus in the CLP + vehicle group compared with the sham groups, whereas apocynin treatment reversed these abnormities. Data are presented as mean ± SEM (n = 6). #p < 0.05 vs the sham groups; *p < 0.05 vs the CLP + vehicle group. Scale bar = 100 μm

Bottom Line:
For the interventional study, the animals were chronically treated with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin, at 5 mg/kg.Primary hippocampal neuronal cultures were used to investigate the mechanisms underlying the dysfunction of PV interneurons.Notably, these abnormalities could be rescued by apocynin treatment.

Background: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by many pathological events, including neuroinflammation and oxidative stress damage. Increasing evidence suggests that parvalbumin (PV) interneurons play a key role in the cognitive process, whereas the dysfunction of these interneurons has been implicated in a number of major psychiatric disorders. Here, we aimed to investigate whether enhanced inflammation and oxidative stress-mediated PV interneuron phenotype loss plays a role in sepsis-induced cognitive impairments.

Methods: Male C57BL/6 mice were subjected to cecal ligation and puncture or sham operation. For the interventional study, the animals were chronically treated with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin, at 5 mg/kg. The mice were euthanized at the indicated time points, and the brain tissues were harvested for determination of the PV, membrane subunit of NADPH oxidase gp91(phox), and markers of oxidative stress (4-hydroxynonenal and malondialdehyde) and inflammation (tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-6, and IL-10). A separate cohort of animals was used to evaluate the behavioral alterations by the open field and fear conditioning tests. Primary hippocampal neuronal cultures were used to investigate the mechanisms underlying the dysfunction of PV interneurons.

Results: Sepsis resulted in cognitive impairments, which was accompanied by selective phenotype loss of PV interneurons and increased gp91(phox), 4-hydroxynonenal, malondialdehyde, IL-1β, and IL-6 expressions. Notably, these abnormalities could be rescued by apocynin treatment.

Conclusion: Selective phenotype loss of PV interneurons, as a result of NADPH oxidase 2 (Nox2) activation, might partly contribute to cognitive impairments in a mouse model of SAE.